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    Por favor, use este identificador para citar o enlazar este ítem:https://uvadoc.uva.es/handle/10324/68995

    Título
    Clinical exome analysis and targeted gene repair of the c.1354dupT variant in iPSC lines from patients with PROM1-related retinopathies exhibiting diverse phenotypes
    Autor
    Puertas Neyra, Kevin LouisAutoridad UVA Orcid
    Coco Martín, Rosa MaríaAutoridad UVA Orcid
    Hernández Rodríguez, Leticia AdriánaAutoridad UVA Orcid
    Gobelli, Dino JoaquinAutoridad UVA
    García Ferrer, Yenisey
    Palma Vecino, Raicel
    Tellería Orriols, Juan JoséAutoridad UVA
    Simarro Grande, MaríaAutoridad UVA
    Fuente García, Miguel Ángel de laAutoridad UVA Orcid
    Fernández Bueno, IvánAutoridad UVA
    Año del Documento
    2024-07-02
    Editorial
    BMC Part of Springer Nature
    Descripción
    Producción Científica
    Documento Fuente
    Stem Cell Res Ther. 2 Jul 2024, vol. 15, n. 1, Article number: 192, 24 páginas.
    Zusammenfassung
    ABSTRACT. BACKGROUND: Inherited retinal dystrophies (IRD) are one of the main causes of incurable blindness worldwide. IRD are caused by mutations in genes that encode essential proteins for the retina, leading to photoreceptor degeneration and loss of visual function. IRD generates an enormous global financial burden due to the lack of understanding of a significant part of its pathophysiology, molecular diagnosis, and the near absence of non-palliative treatment options. Patient-derived induced pluripotent stem cells (iPSC) for IRD seem to be an excellent option for addressing these questions, serving as exceptional tools for in-depth studies of IRD pathophysiology and testing new therapeutic approaches. METHODS: From a cohort of 8 patients with PROM1-related IRD, we identified 3 patients carrying the same variant (c.1354dupT) but expressing three different IRD phenotypes: Cone and rod dystrophy (CORD), Retinitis pigmentosa (RP), and Stargardt disease type 4 (STGD4). These three target patients, along with one healthy relative from each, underwent comprehensive ophthalmic examinations and their genetic panel study was expanded through clinical exome sequencing (CES). Subsequently, non-integrative patient-derived iPSC were generated and fully characterized. Correction of the c.1354dupT mutation was performed using CRISPR/Cas9, and the genetic restoration of the PROM1 gene was confirmed through flow cytometry and western blotting in the patient-derived iPSC lines. RESULTS: CES revealed that 2 target patients with the c.1354dupT mutation presented monoallelic variants in genes associated with the complement system or photoreceptor differentiation and peroxisome biogenesis disorders, respectively. The pluripotency and functionality of the patient-derived iPSC lines were confirmed, and the correction of the target mutation fully restored the capability of encoding Prominin-1 (CD133) in the genetically repaired patient-derived iPSC lines. CONCLUSIONS: The c.1354dupT mutation in the PROM1 gene is associated to three distinct AR phenotypes of IRD. This pleotropic effect might be related to the influence of monoallelic variants in other genes associated with retinal dystrophies. However, further evidence needs to be provided. Future experiments should include gene-edited patient-derived iPSC due to its potential as disease modelling tools to elucidate this matter in question.
    Materias Unesco
    3201.09 Oftalmología
    Palabras Clave
    iPSC, Retinal diseases, PROM1 gene, CD133, Retinitis pigmentosa, Cone-rod dystrophy, Stargardt’s type 4 disease
    ISSN
    1757-6512
    Revisión por pares
    SI
    DOI
    10.1186/s13287-024-03804-2
    Patrocinador
    The study was funded by grant PID2020-118860RB-100 and PID2020-118517RB-I00 funded by MCIN/AEI/https://doi. org/10.13039/501100011033. Programa Estratégico Instituto de Biología y Genética Molecular (IBGM), Junta de Castilla y León (CCVC8485). Consejería de Educación, Junta de Castilla y León (VA172P20). Centro en Red de Medicina Regenerativa y Terapia Celular de Castilla y León. Kevin Puertas-Neyra was funded by predoctoral contracts UVa2020 (co-funded by Santander Bank) and Junta de Castilla y Leon 2021.
    Version del Editor
    https://stemcellres.biomedcentral.com/articles/10.1186/s13287-024-03804-2
    Propietario de los Derechos
    BMC Part of Springer Nature
    Idioma
    eng
    URI
    https://uvadoc.uva.es/handle/10324/68995
    Tipo de versión
    info:eu-repo/semantics/publishedVersion
    Derechos
    openAccess
    Aparece en las colecciones
    • Retina - Artículos de Revista [13]
    • IOBA - Artículos de revista [80]
    • DEP11 - Artículos de revista [242]
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